Repeat length polymorphism of the serotonin
transporter gene influences pulmonary artery pressure
in heart failure
Thomas P. Olson, PhD, Eric M. Snyder, PhD, Robert P. Frantz, MD,
Stephen T. Turner, MD, and Bruce D. Johnson, PhD Rochester, MN
Pulmonary hypertension is common in patients with heart failure (HF); however, for a given degree
of left ventricular dysfunction, the range in pulmonary artery pressures (PAPs) is large. Polymorphisms of the serotonin
transporter (5-HTT) gene have been implicated in contributing to smooth muscle dysfunction and remodeling of the
pulmonary vasculature. This study examined the influence of a repeat length polymorphism in the promoter region of the
5-HTT gene on PAP between patients with HF and healthy control participants.
A total of 90 patients with HF (age, 55 F 14 years; left ventricular ejection fraction, 28% F 10%; New York
Heart Association, 2.0 F 0.9) and 90 age- and sex-matched controls (CTL) (age, 51 F 15 years; left ventricular ejection
fraction, 63% F 7%) were recruited. Patients with HF and CTL participants were divided into 3 genotype groups:
homozygotes for the short variant (SS), homozygotes for the long variant (LL), and heterozygotes (LS). For both HF and CTL,
there are 20 patients in the SS group, 41 in the LS, and 29 in the LL. Pulmonary artery pressure was calculated from the
tricuspid regurgitant velocity.
Age and sex did not differ between the HF and CTL groups. Pulmonary artery pressure was higher in HF
patients compared with CTL (38.9 F 12.5 vs 27.7 F 8.2 mm Hg, respectively; P b .01). There was a significant
interaction between the HF and CTL groups for PAP by genotype ( P b .03), with a significant genotype effect in HF
(SS = 34.2 F 8.6 vs LL = 43.2 F 15.2 mm Hg; P b .05) but not in CTL. The HF group also demonstrated elevated left atrial
diameter compared with CTL (48.0 F 8.7 vs 32.8 F 4.8 mm, respectively; P b .01), although no significant genotype
difference was seen within either group.
These results suggest that the LL variant of the 5-HTT is associated with elevated PAP in patients with HF.
(Am Heart J 2007;153:426232.)
Patients with heart failure (HF) often develop pulmo-
nary abnormalities, including pulmonary arterial hyper-
tension (PAH). Secondary to HF, PAH is a common result
of either systolic or diastolic dysfunction resulting in
elevation of left atrial (LA) pressure, elevated pulmonary
venous pressure, and subsequent elevation of right
ventricular pressure and pulmonary artery pressure
In addition to these classical mechanisms of
elevated PAP in HF, there also appears to be a reactive
component that has been linked to a number of mitogenic
and vasoactive mediators and may also be related to
specific hypoxic mechanisms, both of which are aug-
mented in HF.
Localized hypoxia may be important in
patients with HF because of poor tissue perfusion,
increased ventilation and perfusion mismatch in the
or sleep apnea, the later of which appears to be
highly prevalent in the HF population.
however, for a given degree of left ventricular (LV)
systolic dysfunction, there is large variation in the severity
of pulmonary PAP across patients with HF, which suggest
the potential influence of genetic variation.
Although a number of pathophysiologic mechanisms
for the elevation of PAP have been suggested, serotonin
(5-HT) and its transporter protein (5-HTT) have gained
considerable attention for their contribution to the
etiology of pulmonary hypertension. The effect of 5-HT
on the pulmonary circulation has been examined
extensively in various etiologies of idiopathic PAH.
Specifically, studies have suggested that, in addition to
its vasoactive properties, 5-HT also shows evidence of
From the Mayo Clinic, College of Medicine, Rochester, MN.
The authors of this manuscript have no conflicts of interest to disclose.
Submitted August 25, 2006; accepted December 17, 2006.
Reprint requests: Bruce D. Johnson, PhD, Mayo Clinic, College of Medicine, Rochester,
0002-8703/$ - see front matter
n 2007, Mosby, Inc. All rights reserved.